Laminin receptors and signals in Schwann cells

雪旺细胞中的层粘连蛋白受体和信号

• 批准号: 6752138
• 负责人: M. Laura Feltri
• 金额: $ 23.09万
• 依托单位: FONDAZONE CENT/SAN RAFFAELE/DEL MONTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752138
• 关键词: Schwann cells; axon; biological signal transduction; clinical research; cytoskeleton; gene mutation; genetically modified animals; immunocytochemistry; integrins; laboratory mouse; laminin; myelination; neuromuscular junction; node of Ranvier; proteomics; receptor; video microscopy

DESCRIPTION (provided by applicant): Laminin is important for peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, CMD) and mouse (dystrophic, dy) that manifests both impaired Schwann cell-axon interactions and altered myelination. The molecules that transduce laminin effects in Schwann cells, and the pathomechanisms of laminin mutants remain largely unknown. We have identified several laminin receptors in myelin-forming Schwann cells and shown that they are differentially expressed across peripheral nerve development, suggesting that they subserve differential roles. Our preliminary genetic analysis confirms this notion: Beta1integrin is required for establishing proper Schwann cell-axon relationships prior to birth, whereas dystroglycan is necessary for normal myelination after birth. The Beta1and dystroglycan-null morphological phenotypes suggest that these receptors normally link laminin to cytoskeletal rearrangements in Schwann cells. The overall goal of this proposal is to expand what is known of the molecular basis of laminin-cytoskeletal linkage in Schwann cells. We have produced or collected an unique group of conditional alleles and Cre transgenes that will allow us to disrupt singly or multiply all known major laminin receptors in Schwann cells of transgenic mice. Furthermore, imaging and biochemical analysis of Beta1integrin-null Schwann cells will elucidate how Beta1 directs cytoskeletal rearrangements. Proteomic analysis of Beta1integrin-null Schwann cell/neuron explants will identify candidate signal molecules that link laminin to the cytoskeletal alterations required for axonal interactions. This comprehensive approach will establish the role of the different laminin receptors in peripheral nerve, thereby clarifying the pathogenesis of CMD and dy mutations. The information produced by these experiments will collectively form a basis for developing treatment strategies of CMD and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies.

描述(申请人提供)：层粘连蛋白对周围神经发育和髓鞘形成非常重要。层粘连蛋白突变导致人类(先天性肌营养不良，CMD)和小鼠(营养不良，Dy)的髓鞘障碍神经病，表现为雪旺细胞-轴突相互作用受损和髓鞘形成改变。雪旺细胞中层粘连蛋白效应的转导分子，以及层粘连蛋白突变体的致病机制在很大程度上仍不清楚。我们已经在髓鞘形成的雪旺细胞中发现了几种层粘连蛋白受体，并表明它们在周围神经发育过程中有不同的表达，这表明它们起着不同的作用。我们的初步遗传分析证实了这一观点：β1整合素是在出生前建立适当的雪旺细胞-轴突关系所必需的，而营养不良多糖是出生后正常髓鞘形成所必需的。β1和营养不良糖链缺失的形态表型表明，这些受体通常将层粘连蛋白与雪旺细胞的细胞骨架重排联系起来。这项建议的总体目标是扩大已知的雪旺细胞层粘连蛋白-细胞骨架连接的分子基础。 我们已经产生或收集了一组独特的条件等位基因和Cre转基因基因，这将使我们能够单独或增殖转基因小鼠雪旺细胞中所有已知的主要层粘连蛋白受体。 此外，Beta1整合素缺失的雪旺细胞的成像和生化分析将阐明Beta1如何指导细胞骨架重排。对Beta1整合素缺失的雪旺细胞/神经元外植体的蛋白质组学分析将确定将层粘连蛋白与轴突相互作用所需的细胞骨架改变联系起来的候选信号分子。这一综合方法将确定不同的层粘连蛋白受体在周围神经中的作用，从而阐明CMD和dy突变的发病机制。这些实验产生的信息将共同构成开发CMD和其他遗传性神经疾病的治疗策略的基础，并促进所有神经疾病的神经再生和重新髓鞘形成。